Protective effect of 18β‑glycyrrhetinic acid against H<sub>2</sub>O<sub>2</sub>‑induced injury in Schwann cells based on network pharmacology and experimental validation

Zhang,Di; Sun,Jianxin; Chang,Shiquan; Li,Xing; Shi,Huimei; Jing,Bei; Zheng,Yachun; Lin,Yi; Qian,Guoqiang; Pan,Yuwei; Zhao,Guoping

doi:10.3892/etm.2021.10676

November-2021 Volume 22 Issue 5

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

November-2021 Volume 22 Issue 5

Full Size Image

Article Open Access

Protective effect of 18β‑glycyrrhetinic acid against H₂O₂‑induced injury in Schwann cells based on network pharmacology and experimental validation

Authors:
- Di Zhang
- Jianxin Sun
- Shiquan Chang
- Xing Li
- Huimei Shi
- Bei Jing
- Yachun Zheng
- Yi Lin
- Guoqiang Qian
- Yuwei Pan
- Guoping Zhao
View Affiliations / Copyright

Affiliations: College of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China, College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China, Preventive Treatment of Disease, Tianhe Traditional Chinese Medicine Hospital, Guangzhou, Guangdong 510665, P.R. China

Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 1241
|
Published online on: September 1, 2021

https://doi.org/10.3892/etm.2021.10676
Expand metrics +

Abstract

The aim of the present study was to assess the protective effects of 18β‑GA against hydrogen peroxide (H₂O₂)‑induced injury. First, the SMILES annotation for 18β‑GA was used to search PubChem and for reverse molecular docking in Swiss Target Prediction, the Similarity Ensemble Approach Search Server and the TargetNet database to obtain potential targets. Injury‑related molecules were obtained from the GeneCards database and the predicted targets of 18β‑GA for injury treatment were selected by Wayne diagram analysis. Subsequently, Kyoto Encyclopedia of Genes and Genomes analysis was performed by WebGestalt. The experimental cells were assorted into control, model, 10 µM SB203580‑treated, 5 µM 18β‑GA‑treated and 10 µM 18β‑GA‑treated groups. Hoechst 33258 staining was performed and intracellular reactive oxygen species (ROS) levels, cell apoptosis, Bcl‑xl, Bcl‑2, Bad, Bax, cleaved‑caspase 3, cleaved‑caspase 7, transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) levels, as well as p38 MAPK phosphorylation were measured. The ‘Inflammatory mediator regulation of TRP channels’ pathway was selected for experimental verification. The results indicated that 10 µM 18β‑GA significantly increased cell viability as compared with the H2O2‑treated model group. As suggested by the difference in intracellular ROS fluorescence intensity, 18β‑GA inhibited H₂O₂‑induced ROS production in Schwann cells. Hoechst 33258 staining indicated that 18β‑GA reversed chromatin condensation and the increase in apoptotic nuclei following H₂O₂ treatment. Furthermore, flow cytometry suggested that 18β‑GA substantially inhibited H2O2‑induced apoptosis. Pre‑treatment with 18β‑GA obviously reduced Bad, Bax, cleaved‑caspase3, cleaved‑caspase 7, TRPA1 and TRPV1 levels and p38 MAPK phosphorylation after H₂O₂ treatment and increased Bcl‑2 and Bcl‑xl levels. In conclusion, 18β‑GA inhibited Schwann cell injury and apoptosis induced by H₂O₂ and may be a potential drug to prevent peripheral nerve injury.

View Figures

View References

1	Pastorino G, Cornara L, Soares S, Rodrigues F and Oliveira MBPP: Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review. Phytother Res. 32:2323–2339. 2018.PubMed/NCBI View Article : Google Scholar
2	Abd El-Twab SM, Hozayen WG, Hussein OE and Mahmoud AM: 18β-glycyrrhetinic acid protects against methotrexate-induced kidney injury by up-regulating the Nrf2/ARE/HO-1 pathway and endogenous antioxidants. Ren Fail. 38:1516–1527. 2016.PubMed/NCBI View Article : Google Scholar
3	Su L, Wang Z, Huang F, Lan R, Chen X, Han D, Zhang L, Zhang W and Hong J: 18β-glycyrrhetinic acid mitigates radiation-induced skin damage via NADPH oxidase/ROS/p38MAPK and NF-κB pathways. Environ Toxicol Pharmacol. 60:82–90. 2018.PubMed/NCBI View Article : Google Scholar
4	Mahmoud AM, Hussein OE, Hozayen WG and Abd El-Twab SM: Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγ and Nrf2: Protective effect of 18β-Glycyrrhetinic acid. Chem Biol Interact. 270:59–72. 2017.PubMed/NCBI View Article : Google Scholar
5	Cheng X, Qiu L and Wang F: 18α-glycyrrhetinic acid (GA) ameliorates fructose-induced nephropathy in mice by suppressing oxidative stress, dyslipidemia and inflammation. Biomed Pharmacother. 125(109702)2020.PubMed/NCBI View Article : Google Scholar
6	Zhou J, Cai W, Jin M, Xu J, Wang Y, Xiao Y, Hao L, Wang B, Zhang Y, Han J and Huang R: 18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination. Sci Rep. 5(13713)2015.PubMed/NCBI View Article : Google Scholar
7	Oztanir MN, Ciftci O, Cetin A, Durak MA, Basak N and Akyuva Y: The beneficial effects of 18β-glycyrrhetinic acid following oxidative and neuronal damage in brain tissue caused by global cerebral ischemia/reperfusion in a C57BL/J6 mouse model. Neurol Sci. 35:1221–1228. 2014.PubMed/NCBI View Article : Google Scholar
8	Kao TC, Shyu MH and Yen GC: Glycyrrhizic acid and 18beta-glycyrrhetinic acid inhibit inflammation via PI3K/Akt/GSK3beta signaling and glucocorticoid receptor activation. J Agric Food Chem. 58:8623–8629. 2010.PubMed/NCBI View Article : Google Scholar
9	Gao L, Feng A, Yue P, Liu Y, Zhou Q, Zang Q and Teng J: LncRNA BC083743 promotes the proliferation of Schwann cells and axon regeneration through miR-103-3p/BDNF after sciatic nerve crush. J Neuropathol Exp Neurol. 79:1100–1114. 2020.PubMed/NCBI View Article : Google Scholar
10	Chi GF, Kim DW, Jiang MH, Yoon KJ and Son Y: Schwann-like cells from human melanocytes and their fate in sciatic nerve injury. Neuroreport. 22:603–608. 2011.PubMed/NCBI View Article : Google Scholar
11	Wang L, Sanford MT, Xin Z, Lin G and Lue TF: Role of Schwann cells in the regeneration of penile and peripheral nerves. Asian J Androl. 17:776–782. 2015.PubMed/NCBI View Article : Google Scholar
12	Gonçalves NP, Mohseni S, El Soury M, Ulrichsen M, Richner M, Xiao J, Wood RJ, Andersen OM, Coulson EJ, Raimondo S, et al: Peripheral nerve regeneration is independent from schwann cell p75^NTR expression. Front Cell Neurosci. 13(235)2019.PubMed/NCBI View Article : Google Scholar
13	Gomez-Sanchez JA, Pilch KS, van der Lans M, Fazal SV, Benito C, Wagstaff LJ, Mirsky R and Jessen KR: After nerve injury, lineage tracing shows that myelin and remak schwann cells elongate extensively and branch to form repair Schwann cells, which shorten radically on remyelination. J Neurosci. 37:9086–9099. 2017.PubMed/NCBI View Article : Google Scholar
14	Julien O and Wells JA: Caspases and their substrates. Cell Death Differ. 24:1380–1389. 2017.PubMed/NCBI View Article : Google Scholar
15	Kalkavan H and Green DR: MOMP, cell suicide as a BCL-2 family business. Cell Death Differ. 25:46–55. 2018.PubMed/NCBI View Article : Google Scholar
16	Li ZY, Tung YT, Chen SY and Yen GC: Novel findings of 18β-glycyrrhetinic acid on sRAGE secretion through inhibition of transient receptor potential canonical channels in high-glucose environment. Biofactors. 45:607–615. 2019.PubMed/NCBI View Article : Google Scholar
17	Wankun X, Wenzhen Y, Min Z, Weiyan Z, Huan C, Wei D, Lvzhen H, Xu Y and Xiaoxin L: Protective effect of paeoniflorin against oxidative stress in human retinal pigment epithelium in vitro. Mol Vis. 17:3512–3522. 2011.PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
19	Zhang D, Sun J, Yang B, Ma S, Zhang C and Zhao G: Therapeutic effect of tetrapanax papyriferus and hederagenin on chronic neuropathic pain of chronic constriction injury of sciatic nerve rats based on KEGG pathway prediction and experimental verification. Evid Based Complement Alternat Med. 2020(2545806)2020.PubMed/NCBI View Article : Google Scholar
20	Gouin O, L'Herondelle K, Lebonvallet N, Le Gall-Ianotto C, Sakka M, Buhé V, Plée-Gautier E, Carré JL, Lefeuvre L, Misery L and Le Garrec R: TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: Pro-inflammatory response induced by their activation and their sensitization. Protein Cell. 8:644–661. 2017.PubMed/NCBI View Article : Google Scholar
21	Wang M, Zhang Y, Xu M, Zhang H, Chen Y, Chung KF, Adcock IM and Li F: Roles of TRPA1 and TRPV1 in cigarette smoke-induced airway epithelial cell injury model. Free Radic Biol Med. 134:229–238. 2019.PubMed/NCBI View Article : Google Scholar
22	Ma G, Luo W, Lu J, Ma DL, Leung CH, Wang Y and Chen X: Cucurbitacin E induces caspase-dependent apoptosis and protective autophagy mediated by ROS in lung cancer cells. Chem Biol Interact. 253:1–9. 2016.PubMed/NCBI View Article : Google Scholar
23	Kang N, Wang MM, Wang YH, Zhang ZN, Cao HR, Lv YH, Yang Y, Fan PH, Qiu F and Gao XM: Tetrahydrocurcumin induces G2/M cell cycle arrest and apoptosis involving p38 MAPK activation in human breast cancer cells. Food Chem Toxicol. 67:193–200. 2014.PubMed/NCBI View Article : Google Scholar
24	Sun Y, Liu WZ, Liu T, Feng X, Yang N and Zhou HF: Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res. 35:600–604. 2015.PubMed/NCBI View Article : Google Scholar
25	Coskun AK, Yigiter M, Oral A, Odabasoglu F, Halici Z, Mentes O, Cadirci E, Atalay F and Suleyman H: The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. ScientificWorldJournal. 11:1341–1356. 2011.PubMed/NCBI View Article : Google Scholar
26	Ishida T, Mizushina Y, Yagi S, Irino Y, Nishiumi S, Miki I, Kondo Y, Mizuno S, Yoshida H, Azuma T and Yoshida M: Inhibitory effects of glycyrrhetinic acid on DNA polymerase and inflammatory activities. Evid Based Complement Alternat Med. 2012(650514)2012.PubMed/NCBI View Article : Google Scholar
27	Ishida T, Miki I, Tanahashi T, Yagi S, Kondo Y, Inoue J, Kawauchi S, Nishiumi S, Yoshida M, Maeda H, et al: Effect of 18β-glycyrrhetinic acid and hydroxypropyl γcyclodextrin complex on indomethacin-induced small intestinal injury in mice. Eur J Pharmacol. 714:125–131. 2013.PubMed/NCBI View Article : Google Scholar
28	Khezri MK, Turkkan A, Koc C, Salman B, Levent P, Cakir A, Kafa IM, Cansev M and Bekar A: Anti-apoptotic and anti-oxidant effects of systemic uridine treatment in an experimental model of sciatic nerve injury. Turk Neurosurg. 31:373–378. 2021.PubMed/NCBI View Article : Google Scholar
29	Zhang D, Yang B, Chang SQ, Ma SS, Sun JX, Yi L, Li X, Shi HM, Jing B, Zheng YC, et al: Protective effect of paeoniflorin on H₂O₂ induced Schwann cells injury based on network pharmacology and experimental validation. Chin J Nat Med. 19:90–99. 2021.PubMed/NCBI View Article : Google Scholar
30	Kalinski AL, Yoon C, Huffman LD, Duncker PC, Kohen R, Passino R, Hafner H, Johnson C, Kawaguchi R, Carbajal KS, et al: Analysis of the immune response to sciatic nerve injury identifies efferocytosis as a key mechanism of nerve debridement. Elife. 9(e60223)2020.PubMed/NCBI View Article : Google Scholar

Journals